title: Chemical synthesis of hydrocarbon-stapled peptides for protein interaction research and therapeutic targeting.
abstract: The peptide α-helix represents one of nature's most featured protein shapes and is employed in a diversity of protein architectures, from the cytoskeletal infrastructure to the most intimate contact points between crucial signaling proteins. By installing an all-hydrocarbon crosslink into native sequences, the shape and biological activity of natural peptide α-helices can be recapitulated, yielding a chemical toolbox that can be used both to interrogate the protein interactome and to modulate interaction networks for potential therapeutic benefit. Here, current methodology for synthesizing stabilized α-helices (SAH) corresponding to key protein interaction domains is described. A stepwise approach is taken for the production of crosslinking non-natural amino acids, incorporation of the residues into peptide templates, and application of ruthenium-catalyzed ring-closing metathesis to generate hydrocarbon-stapled peptides. Through facile derivatization and functionalization steps, SAHs can be tailored for a broad range of applications in biochemical, structural, proteomic, cellular, and in vivo studies. Curr. Protoc. Chem. Biol. 3:99-117 © 2011 by John Wiley & Sons, Inc.
authors.affiliation: Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, Boston, Massachusetts.
authors.forename: Gregory H
authors.initials: GH
authors.lastname: Bird
authors.forename: W Christian
authors.initials: WC
authors.lastname: Crannell
authors.forename: Loren D
authors.initials: LD
authors.lastname: Walensky
keywords: hydrocarbon stapling; olefin metathesis; peptide; photoreactive; protein interaction; targeting; α‐helix